Development of subclinical myocardial dysfunction and progression to overt left ventricular systolic dysfunction (LVSD) and heart failure (HF) represent a major and growing healthcare burden. Often a long-term complication of atherosclerotic heart disease, LVSD and HF may also develop in the absence of significant angiographic evidence of coronary artery disease. The underlying pathophysioplogical mechanisms contributing to development of LVSD and HF are multifactoral. Interestingly, treatment of HF with nitric oxide (NO) donors such as nitrates has shown a resurgence in use due to demonstrated added clinical efficacy on top of traditional neurohormonal antagonist therapy. There has been long-standing recognition that NO related processes play a role in the development and progression of ischemic and non-ischemic HF, though most data focuses on studies of advanced HF subjects. Little is known about the role of NO related pathways, including formation of NO-derived oxidants (aka nitrative stress) in the development of subclinical myocardial dysfunction, LVSD and HF. Our overall goal is to test the hypothesis that nitrative stress and specific NO-related processes are mechanistically linked to the development of ischemic and non-ischemic HF in order to facilitate both identification and preventive treatment efforts for subjects at risk of developing LVSD and HF. This will be achieved by employing a combination of biochemical and mass spectrometry-based analyses of human clinical specimens with extensive clinical phenotypic data. We will leverage access to a large (N>10,000) and well characterized cohort of cardiovascular subjects, GeneBank, at our institution for performance of the following specific aims: Aim 1. To test the hypothesis that baseline levels of specific NO-mediated processes are associated with the presence of subclinical myocardial dysfunction, LVSD and HF in stable patients. Aim 2. To test the hypothesis that baseline and interval changes in specific NO-mediated processes are associated with prospective risks for development of subclinical myocardial dysfunction, LVSD (as detected by comprehensive echocardiography), and HF amongst individuals without LVSD/HF at baseline. PUBLIC HEALTH RELEVANCE: The present will help identify specific nitrative stress pathway of clinical relevance with mechanistic links to cardiovascular disease pathogenesis and adverse sequelae such as heart failure and left ventricular systolic dysfunction. Successful completion of the proposed studies will provide mechanistic and clinical insights into defining individuals at risk for the development of subclinical myocardial dysfunction, left ventricular systolic dysfunction, and heart failure, as well as additional potential therapeutic targets for reducing the risk for developing subclinical myocardial dysfunction, left ventricular systolic dysfunction, heart failure, and long-term adverse complications.